Tetrazole derivatives bearing benzodiazepine moiety-synthesis and action mode against virulence of Candida albicans.

Tetrazole and benzodiazepine derivatives attract widespread attention due to their remarkable pharmaceutical potential. 5-(2-bromophenyl)-7-fluoro-1-[3-(5-(4-chlorophenyl)-2H-tetrazol-2-yl)propyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one (6c) and 5-(2-bromophenyl)-7-fluoro-1-[3-(5-(2-chlorophenyl)-2H-tetrazol-2-yl)propyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one (6d) were selected using the microdilution approach and because of their preferential fungicidal activity toward C. albicans. 6c or 6d altered the hyphal morphology, chitin deposition and membrane permeation in planktonic and sessile cells. The tetrazoles caused PS translocation and the accidental dependent permeabilization (ADP) of sessile cells; 6d showed CNB1-dependent action in candidiasis. The exosome Rh123-rich vesicles extruded out of the membrane as an element of the self-defense detoxification strategy when the treatment, especially with 6d, was conducted. The tetrazoles affected the C. albicans biofilm's viability, and Rh123 sequestrates led to a heterogenous sub-cellular localization. While 6c-dependent sequestration into membranes or sub-cellular organelles was noted, Rh123 cellular loading in control cells and distributed within cells was observed (partitioning into subcellular membranes and organelles in apoptotic cells). In conclusion, we propose new agents aimed at Candida virulence factors triggering ACD without toxicity against eukaryotic cells.

Biological properties and structural study of new aminoalkyl derivatives of benzimidazole and benzotriazole, dual inhibitors of CK2 and PIM1 kinases.

The new aminoalkyl-substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl-derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines - CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC50 is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α1-335/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Šresolution, what enabled the determination of the corresponding 3D-structures.